Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions.

ABSTRACT: Although glucose, through pentose phosphate pathway (PPP), is the main source to generate NADPH, solid tumors are often deprived of glucose, hence alternative metabolic pathways to maintain NADPH homeostasis in cancer cells are required. Here, we report that lactate and glutamine support NADPH production via isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), respectively, under glucose-deprived conditions. Isotopic tracing demonstrates that lactate participates in the formation of isocitrate. Malate derived from glutamine in mitochondria shuttles to cytosol to produce NADPH. In cells cultured in the absence of glucose, knockout of IDH1 and ME1 decreases NADPH/NADP⁺ and GSH/GSSG, increases ROS level and facilitates cell necrosis. In 4T1 murine breast tumors, knockout of

SUBMITTER: Ying M 

PROVIDER: S-EPMC8321918 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature